The long-term goal of this proposal is to define the molecular mechanisms that promote axonal degeneration following injury or disease. Axonal degeneration is a common feature of many neurological diseases. Neuropathies due to axonal degeneration are a hallmark of disorders such as diabetes, glaucoma, and chemotherapy-induced neurotoxicity and axonal loss is an early feature of debilitating neurodegenerative diseases. The great length of many axons makes them particularly vulnerable to mechanical injury, and axonal degeneration following trauma is a major cause of disability. Recent studies demonstrate that axonal degeneration is an active and highly regulated process, yet the intrinsic, neuronal mechanism promoting degeneration is poorly understood. This proposal investigates what causes axons to degenerate, and how this can be prevented. Axonal degeneration is an active process of self-destruction that appears to be naturally primed and waiting for a triggering stimulus that activates the execution phase. It proceeds as a stepwise process that begins with microtubule destabilization, followed by rapid blebbing of the axonal membrane, axonal fragmentation, cytoskeletal degradation and eventual engulfment by glial and/or phagocytic cells. We now demonstrate that the DLK pathway functions in the intrinsic neuronal pathway that promotes axonal degeneration following injury. Identifying and characterizing the function of components of the intrinsic axonal degeneration pathway will provide insights into its mechanism as well as potential therapeutic targets for the many neurological diseases characterized by axonal degeneration.